Not applicable.
Certain homovanilloid compounds, notably the homovanillyl diterpene esters resiniferatoxin (RTX) and tinyatoxin (TYX) are known to have physiological effects similar to capsaicin (CAP). Depending on which physiological response is measured, the homovanilloids are more potent than CAP, on a molar basis, by a factor of 10-10,000. In particular, RTX, TYX and other homovanilloids have been shown to be effective for desensitizing sensory nerves in a manner similar to CAP but at lower dosage (U.S. Pat. Nos. 4,939,149 and 5,021,450, incorporated herein by reference).
Urinary incontinence, the inability to maintain voluntary control of micturition, is a condition affecting millions of men and women. The control of micturition is a complex physiological process including neural reflex pathways, some with and some without central nervous system control, smooth and voluntary muscles and hormonal effects. (See review by DeGroat, [1997] Urology 50[Supplement 6A]:36-52.) A large subset of urinary incontinence is at least partly neurogenic. The clinical term xe2x80x9coveractive bladderxe2x80x9d is used generally to denote any form of incontinence characterized by increased frequency of micturition or desire to void, whether complete or episodic, and where loss of voluntary control ranges from partial to total. xe2x80x9cUrge incontinencexe2x80x9d is the involuntary loss of urine associated with an abrupt and powerful desire to void. Urge incontinence is usually, but not always, associated with the urodynamic finding of involuntary (uninhibited) contractions of the detrusor muscle. The detrusor muscle provides the primary force in expelling urine from the bladder. A large subset of patients with uninhibited detrusor have some sort of neurologic impairment, in which case the clinical term is xe2x80x9cdetrusor hyperreflexiaxe2x80x9d (DH). The term detrusor instabilityxe2x80x9cor xe2x80x9cunstable detrusorxe2x80x9d is reserved for conditions where there is no neurologic abnormality. There is evidence suggesting that detrusor instability may result from subclinical neurologic disease or from primary muscle disease (Payne, C. K. [1998] Urology 51[Suppl.2A]:3-10). Common neurologic disorders associated with detrusor hyperreflexia (DH) are Parkinson""s disease, stroke, diabetes, multiple sclerosis (MS), peripheral neuropathy and spinal cord injury.
Other types of urinary incontinence result from hypersensitivity of sensory (afferent) neurons of the urinary bladder. The desire to void and the reflexes resulting in micturition are initiated by (afferent) inputs from the urinary bladder including C-fiber transmitted afferent impulses. Certain inflammatory conditions, hormonal imbalance, prostate hypertrophy and the like can cause afferent hypersensitivity of the neurons of the bladder, resulting in increased frequency, unexpected urgency, and the like, leading to incontinence episodes of varying severity. Both DH and sensory hypersensitivity are included in the term xe2x80x9cneurogenic urinary dysfunctionxe2x80x9d herein.
CAP has been used to treat patients with detrusor hyperreflexia (DH), by intravesical instillation. However, CAP is not suitable for routine usage in incontinence because there is intense burning and pain in the lower abdomen upon instillation, and there is a period of 2-4 days after treatment when symptoms actually deteriorate before any improvement is noted.
RTX has been tested in rats to assess possible efficacy in humans. Buck et al. (1990) International patent publication WO 90/14083, described studies designed to assess desensitizing effects of administering RTX into rat urinary bladders. The animals were anesthetized prior to perfusing the bladders with RTX. An immediate excitatory stage was observed upon initial perfusion, followed by decreasing excitation upon subsequent perfusions, indicating that desensitization was occurring. The use of local anesthetics to alleviate pain during RTX administration was discussed.
Ishizuka et al. (1995) J. Urol. 154:611-616 described studies demonstrating RTX-induced desensitization of vanilloid receptor-mediated release of tachykinins in the rat urinary bladder. Differences between the physiologic effects of RTX and CAP were noted. Desensitization to repeated doses of RTX was observed, but not to repeated doses of CAP. CAP was effective in reducing symptoms in rats having an experimentally induced hypertrophy, whereas RTX was not. RTX was stated to be 1000 times more potent than CAP.
Craft et al. (1994a) Physiol and Behavior 56:479-485 reported studies indicating pain induced by intravesical administration of RTX to rats. Both excitatory and desensitizing effects of CAP and RTX were attenuated by ruthenian red, a known cation channel blocker.
Craft et al. (1994b) Pain 57:351-359 reported tests to demonstrate that local anesthetics could reduce pain associated with administering RTX intravesicularly to rats.
Craft et al. (1995) Pain 61:317-323 described studies showing long-lasting desensitization of bladder afferents in rats treated with intravesicular CAP (10-100 xcexcmol) or RTX (10-100 xcexcmol).
Lazzeri et al. (1996) Urodinamica 6:107-109 reported studies on intravesicular administration of 10xe2x88x928M (0.01 xcexcM) RTX to normal human volunteers and patients with unstable detrusor. Normal patients reported no warn or burning sensation upon administration, and no changes in bladder function. Three of five patients having unstable detrusor reported an increased volume required to elicit first desire to void, while two patients had no significant urodynamic results. At the RTX concentration employed, the human subjects experienced no micturition reflex or burning upon administration, in contrast to reports in rats.
The invention is based on experimental evidence of effective therapy of humans experiencing neurogenic urinary dysfunction, including urge and mixed urge incontinence. The therapy includes intravesicular instillation of certain homovanilloid compounds, including resiniferatoxin (RTX), tinyatoxin (TYX), 20-homovanillyl-mezerein and 20-homovanillyl-12-deoxyphorbol-13-phenylacetate. Patients who benefit from the therapy include those with impairment of the micturition reflex, in particular those whose impairment involves the afferent branch of the reflex and those with hypersensitivity of bladder afferent nerves or C-fiber-transmitted sensory impulses. The therapy is effective for patients who have spinal cord damage, either due to trauma or related to disease, including, without limitation, inflammatory, auto-immune, vascular, metabolic, prostate hypertrophy, interstial systitis, genetic disease and infectious disease. The therapy is especially effective for patients whose incontinence is due to multiple sclerosis.
In general, treatment is conducted by administering RTX (or a functionally equivalent analog such as TYX) topically to the urinary bladder mucosa, by intravesicular instillation. A solution of a therapeutically effective amount of the compound (e.g. RTX) is retained in the bladder for a convenient time interval, e.g. about one hour, then excreted. A single such treatment can be effective for an extended period, such that a patient can be maintained by treatments once every 1-6 months. A major unexpected advantage of the use of RTX or its analog is that when administered at effective dosage the compounds do not cause pain or burning sensations, such as are associated with CAP treatment. Furthermore, patients experience no initial deterioration of their symptoms as is the case with CAP treatment. The therapy is therefore more tolerable and longer-lasting, compared to CAP treatment.